The neuropeptide slow transmitter PACAP (pituitary adenylate cyclase activating polypeptide) is released at synapses that transduce stress responses to the brain, and mediate homeostatic adjustments to stress by the organism. Allostatic responses to systemic and psychogenic stressors at multiple points in development and throughout the life span are implicated as causative factors in depression and post-traumatic stress disorder (PTSD). Stress response pathways (resilience responses) may also be required to ameliorate delayed neuronal death (DND) in traumatic brain injury, long-term exposure to intense physical or psychological stimuli, or brain inflammation in chronic neurodegenerative disease. Understanding the cellular mechanisms of stress transduction is crucial to developing effective therapeutic interventions for these disorders. Having in the previous year identified the specific contributions of the three major cAMP sensors PKA, Epac (Rapgef2 3 and 4), and NCS/Rapgef2 to major cAMP-dependent processes carried out by NS-1 neuroendocrine cells and primary neurons in cellula (A.C. Emery, M.V. Eiden and L.E. Eiden, J.Biol. Chem. 289: 10126, 2014), we have now begun efforts to determine the relative contributions of the three sensors to cAMP-dependent effects mediated by the Gs-coupled PACAP receptor PAC1 and the dopamine receptor D1, in the extended amygdala and in the ventral striatum, respectively, during the processes of development of chronic stress-induced depressive behavior, and psychomotor stimulant-induced plasticity of medium spiny neurons, respectively.